6-hydroxymethyl-15beta 16beta-methylene pregnenes and process

ABSTRACT

MEDICINALLY VALUABLE 6-METHYLI15B, 16B-METHYLENE PREGNENES ARE OBTAINED FROM NOVEL CORRESPONDINGLY SUBSTITUTED 6-HYDROXYMETHYL-15B,16B-METHYLENE PREGENES BY A TWO STEP PROCEDURE. THE 6-HYDROXYMETHYL-15B,16BMETHYLENE PREGNENES ARE OBTAINED BY TREATMENT OF A 6UNSUBSTITUTED-15B,16B-METHYLENE PREGNENE WITH FORMALDEHYDE.

United States Patent O US. Cl. 260397.4 6 Claims ABSTRACT OF THEDISCLOSURE Medicinally valuable -6-methyl-l5B,l6B-methylene pregnenesare obtained from novel correspondingly substituted6-hydroxymethyl-l55,16,8-methylene pregnenes by a two step procedure.The 6-hydroxymethyl-l5 8,l6;8- methylene pregnenes are obtained bytreatment of a 6- unsubstituted-lS B,16,8-methylene pregnene withformaldehyde.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates tonovel steroids of the formula c3 II where R is hydrogen or halogen; R ishydroxy, acyloxy or alkoxy; R is hydrogen, halogen, hydroxy, acyloxy oralkoxy and R both are either hydrogen or methyl.

The above compound of Formula II are useful as intermediates in thepreparation of medicinally valuable steroids of the following formulawhere R R R and R are as above.

The compound of Formula I above exhibit hormonal activity and are usefulas medicaments. They are de Patented Feb. 22, 1972 "ice scribed ingreater detail in co-pending application Ser. No. 817,178, filed April17, 1969, title 15,16-Substituted Steroids and Derivatives, inventors,Andor Fiirst et al.

As used herein, the term acyloxy is meant to include a group containingthe residue of a saturated or unsaturated aliphatic, cycle-aliphatic,araliphatic or aromatic carboxylic acids having up to 20 carbon atoms,preferably up to 12 carbon atoms. Examples of such acids include formicacid, acetic acid, pivalic acid, propionic acid, butyric acid, caproicacid, enanthic acid, oleic acid, palmitic acid, stearic acid, succinicacid, malonic acid, citric acid and benzoic acid.

The term alkoxy is meant to include groups having up to 10 carbon atomswhich can be of aliphatic, cycloaliphatic or araliphatic nature.Examples of suitable alkoxy groups for the practice of this inventioninclude the rnethoxy, ethoxy, propoxy, butoxy and isomers such astertiary butoxy, cyclopentyloxy, cyclohexyloxy and benzyloxy groups,among others.

The term halogen is meant to include fluorine, chlorine, bromine andiodine with fluorine, chlorine and bromine being the halogens ofpreference.

A preferred subgenus of the compounds of Formula II is obtained when Rboth are hydrogen. Preferred compounds within that subgenus are obtainedwhen R and R are hydrogen and R is acetoxy. Compounds of Formula II ofthe present invention can be readily prepared by reacting a steroid ofthe formula where R R R and R are as above and R represents a residue ofa secondary amine linked via the nitrogen atom with formaldehyde.

The reaction of a steroid of Formula IV with formaldehyde can beconveniently conducted by treating such steroidal starting materialdissolved in a suitable solvent such as, for example, an aromatichydrocarbon, e.g., benzene or toluene; an ether such as dioxane ortetrahydrofuran; or a lower aliphatic alcohol such as methanol orethanol, with aqueous formaldehyde solution.

Steroids of Formula IV, where not otherwise available, may be readilyprepared from a corresponding 3-keto-A steroid in a manner known per seby reacting the latter with a secondary amine, for example, with adi-(lower aliphatic)amine such as dimethylamine or diethylamine or,especially a 5- or 6-membered cyclic amine which can contain a furtherhereto atom, such as pyrrolidine, piperidine and morpholine.

The conversion of compounds of Formula II to compounds of Formula I canbe readily accomplished by means of a two step procedure. In the firststep compounds of Formula II are dehydrated to yield a steroid of theformula III where R R R and R are as above.

The aforesaid dehydration can be carried out utilizing acid treatment.Suitable acids for this purpose include mineral acids, such ashydrochloric acid or strong organic acids, such as, for example, thesulfonic acids, e.g., ptoluenesulfonic acid. The dehydration procedurecan be carried out in a suitable solvent such as, for example, aromatichydrocarbons such as benzene or toluene, ethers such as dioxan ortetrahydrofuran or lower aliphatic alcohols such as methanol or ethanol.

The conversion of compounds of Formula III to compounds of Formula Iinvolves an isomerization procedure involving the 6-methylene group inthe compounds of Formula III. This isomerization utilizes a catalyst,such as a hydrogenation catalyst, most preferably palladium. Thehydrogen donator such as cyclohexene may be added to the reactionmixture to serve as an activator for the catalyst. Undesiredside-reactions such as hydrogenations by the hydrogen donor can beavoided by buffering the reaction mixture.

The present invention is further illustrated by the following example.

EXAMPLE 1 A mixture of 1.0 g. ofl7a-acetoXy-155,l6/8-methylenepregn-4-ene-3,20-dione, 0.5 ml. ofpyrrolidine, 30 mg. of p-toluenesulfonic acid and 15 ml. of benzene washeated to reflux for hours using a water-separator. The mixture wascooled to room temperature, ml. of ether was added and the mixture wasallowed to stand for 15 minutes. The mixture was filtered and thefiltrate evaporated in vacuo. A total of 1.2 g. of crystalline17a-acetoxy-15p, 16p-methylene 3 pyrrolidino-pregna 3,5 dien-20-one wereobtained, e =14,000. This material was dissolved in 40 ml. of benzeneand 80 ml. of absolute alcohol. With stirring, 1.6 ml. of 40 percentaqueous formaldehyde solution was added dropwise to the solution at roomtemperature over 5 minutes. The mixture was subsequently stirred for afurther minutes and then evaporated in vacuo. Chromatography of theresidue on 60 g. of silica gel with benzene-acetone 5:1 yielded pure17ot-acetoxy-6fihydroxymethyl-lSfl,l6fi-methylene-pregn 4 cue-3,20-dione, M.P. 234236 C. (from acetone-hexane), 6 16,500; [a] =51 (c.=0.lin dioxane).

EXAMPLE 2 A total of 0.65 ml. of water and 0.65 ml. of concentratedhydrochloric acid were added to a solution of 414 mg. of 17u-acetoxy 6,3hydroxymethyl 155,165-methy1- ene-pregn-4-ene-3,20-dione in ml. ofdioxan. The mixture was held at room temperature for two and one-halfhours. A total of 2.0 g. of sodium bicarbonate were added and themixture was stirred for 15 minutes and filtered. The filtrate wasevaporated in vacuum and the residue recrystallized from acetone-hexane.The pure 17a-acetoxy- 6,15,6,16p-bismethylene-pregn 4 ene-3,20-dionemelted at 199201 C. e =12,1QO [a] (c.=0.1 in dioxane).

A total of 10 ml. of ethanol containing 0.5 percent cyclohexene wasadded dropwise over a period of five hours with stirring and heating toreflux to a mixture of 0.5 g. of 17u-acetoxy6,1513,16fi-bis-methylenepregn- 4-ene-3,20-dione, 250 mg. of sodiumacetate, 25 mg. of 5 percent palladium on charcoal and 15 ml. ofethanol. The reaction mixture was filtered and the filtrate evaporatedto dryness. The crude product was chromatographed on 75 g. of silicagel. Elntion with hexane-ether yielded pure 17u-acetoxy 6 methyl 155,166methylenepregna-4,6-diene-3,20-dione melting at 191-l92 C. afterrecrystallization from acetone-hexane. e =23,500; [a] =78 (c.=().l indioxane).

We claim:

1. The compounds of the formula:

Cli OII CH OH where R is hydrogen or halogen; R is hydroxy, C acyloxy orC all-:oxy; R is hydrogen, halogen, hydroxy, C acyloxy or C alkoxy and Rboth are either hydrogen or methyl which process comprises reacting acompound of the the mtrogen atom; and R174 and 2 are as formula shownabove with formaldehyde.

6. The process of claim 5 wherein R, R and R are 5 hydrogen; R isacetoxy and R is pyrrolidino.

References Cited UNITED STATES PATENTS 10 3,328,433 6/1967 Cooley et a1260397.4 3,389,154 6/1968 Barn et a1. 260397.45

HENRY A. FRENCH, Primary Examiner US. Cl. X.R.

where R, is a residue of a secondary amine linked via 15 260-397.47, 999

